PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION IBRANCE. 75 mg, 100 mg and 125 mg capsules. Protein Kinase Inhibitor

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1 PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION Pr IBRANCE Palbociclib capsules 75 mg, 100 mg and 125 mg capsules Protein Kinase Inhibitor IBRANCE, indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease, has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization. For further information for IBRANCE please refer to Health Canada s Notice of Compliance with conditions - drug products web site: IBRANCE, indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed after prior endocrine therapy, has been issued marketing authorization without conditions. Pfizer Canada Inc Trans-Canada Highway Kirkland, Quebec H9J 2M5 Date of Preparation: May 19, 2017 Submission Control No: TM Pfizer Inc. Pfizer Canada Inc., Licensee IBRANCE Product Monograph Page 1 of 45

2 This product has been authorized under the Notice of Compliance with Conditions (NOC/c) What is a Notice of Compliance with Conditions (NOC/c)? An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada. Products approved under Health Canada s NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame. What will be different about this Product Monograph? The following Product Monograph will contain boxed text at the beginning of each major section clearly stating the nature of the market authorization. Sections for which NOC/c status holds particular significance will be identified in the left margin by the symbol NOC/c. These sections may include, but are not limited to, the following: - Indications and Clinical Uses; - Action; - Warnings and Precautions; - Adverse Reactions; - Dosage and Administration; and - Clinical Trials. Adverse Drug Reaction Reporting and Re-Issuance of the Product Monograph Health care providers are encouraged to report Adverse Drug Reactions associated with normal use of these and all drug products to Health Canada s Canada Vigilance Program at The Product Monograph will be re-issued in the event of serious safety concerns previously unidentified or at such time as the sponsor provides the additional data in support of the product s clinical benefit. Once the latter has occurred, and in accordance with the NOC/c policy, the conditions associated with market authorization will be removed. IBRANCE Product Monograph Page 2 of 45

3 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 4 SUMMARY PRODUCT INFORMATION... 4 INDICATIONS AND CLINICAL USE... 4 CONTRAINDICATIONS... 5 WARNINGS AND PRECAUTIONS... 5 ADVERSE REACTIONS... 9 DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY SPECIAL HANDLING INSTRUCTIONS DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY TOXICOLOGY REFERENCES PART III: PATIENT MEDICATION INFORMATION IBRANCE Product Monograph Page 3 of 45

4 Pr IBRANCE Palbociclib capsules PART I: HEALTH PROFESSIONAL INFORMATION IBRANCE, indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization. For further information for IBRANCE please refer to Health Canada s Notice of Compliance with conditions - drug products web site: IBRANCE, indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed after prior endocrine therapy, has been issued marketing authorization without conditions. SUMMARY PRODUCT INFORMATION Route of Administration Oral Pharmaceutical Form/Strength Capsules 75 mg, 100 mg, 125 mg Clinically Relevant Nonmedicinal Ingredients Lactose monohydrate For a complete listing see Dosage Forms, Composition and Packaging section. INDICATIONS AND CLINICAL USE IBRANCE (palbociclib) is indicated: NOC/c in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)- negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer whose disease progressed after prior endocrine therapy. Pre- or perimenopausal women must also be treated with a luteinizing hormone releasing hormone (LHRH) agonist. IBRANCE Product Monograph Page 4 of 45

5 Geriatrics ( 65 years of age): In clinical trials, of 84 patients who received IBRANCE plus letrozole, 37 patients (44%) were 65 years of age. Of 347 patients who received IBRANCE plus fulvestrant, 86 patients (25%) were 65 years of age. No overall differences in the efficacy of IBRANCE were observed between these patients and younger patients in either study. Neutropenia and leukopenia (all grades and Grades 3 and 4) were reported more frequently in patients 65 than in patients <65 years of age treated with IBRANCE plus letrozole, whereas similar incidences were reported for these parameters in both age groups for patients treated with IBRANCE plus fulvestrant. Pediatrics (< 18 years of age): Safety and efficacy of IBRANCE in children and adolescents <18 years have not been studied. NOC/c CONTRAINDICATIONS Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. NOC/c WARNINGS AND PRECAUTIONS Serious Warnings and Precautions IBRANCE (palbociclib) should be prescribed and managed by a qualified physician who is experienced in the use of anti-cancer agents. The following is a significant adverse drug reaction identified in clinical trials conducted with IBRANCE: Neutropenia (see Hematologic section below) General Effects on ability to drive and use machines No studies of the effects of IBRANCE (palbociclib) on the ability to drive or operate machinery have been conducted. However, since fatigue and dizziness have been reported with the use of IBRANCE, patients should exercise caution when driving or operating machinery while taking IBRANCE. Carcinogenesis and Mutagenesis Carcinogenicity studies have not been conducted with IBRANCE. IBRANCE Product Monograph Page 5 of 45

6 Cardiovascular Cardiac Electrophysiology In the in vivo cardiovascular safety pharmacology studies conducted in dogs, QTc interval prolongation was highly correlated with the plasma exposure to palbociclib. An unbound plasma concentration of 67 ng/ml was associated with a 5 msec increase in QTc (approximately 4 times the unbound steady-state human C max ) (see DETAILED PHARMACOLOGY). The effect of palbociclib on QTc was evaluated through a pharmacokinetic/pharmacodynamic analysis using data from 184 patients with advanced cancer. At the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (e.g., 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days), the mean QTcS increase was 5.60 msec and the upper bound of the 1-sided 95% confidence interval (CI) was 8.72 msec. Clinically relevant QT prolongation due to palbociclib is unlikely. A dedicated ECG substudy is ongoing. Hematologic Neutropenia Neutropenia was the most frequently reported adverse reaction in patients treated with IBRANCE plus letrozole (75%) or IBRANCE plus fulvestrant (83%). Grade 3 decreased neutrophil counts were observed in approximately half of all patients, and Grade 4 decreased neutrophil counts were observed in 5% and 11% of patients treated with IBRANCE in combination with letrozole or fulvestrant, respectively [see ADVERSE REACTIONS]. The median time to first episode of any grade neutropenia was 15 days, and the median duration of Grade 3 neutropenia was 7 days. Febrile neutropenia has been reported in about 1% of patients treated with IBRANCE plus fulvestrant, and has not been reported in patients treated with IBRANCE plus letrozole. One patient treated with IBRANCE plus fulvestrant died due to neutropenic sepsis. Physicians should inform patients to promptly report any episodes of fever. Monitor complete blood count prior to the start of IBRANCE therapy, at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated [see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests]. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see DOSAGE AND ADMINISTRATION]. For patients who experience Grade 3 neutropenia, consider repeating complete blood count monitoring one week later. Other Hematologic Parameters Decreases in leukocytes and platelets were observed in patients treated with either IBRANCE plus letrozole or IBRANCE plus fulvestrant. Grade 3 leukopenia was reported in 19% of IBRANCE plus letrozole patients and in 30% of IBRANCE plus fulvestrant patients. Decreased hemoglobin and lymphocytes were also observed in IBRANCE plus letrozole-treated patients [see ADVERSE REACTIONS]. IBRANCE Product Monograph Page 6 of 45

7 Anemia and leukopenia were usually managed with temporary IBRANCE discontinuation and/or dose reduction. Monitor complete blood count prior to the start of IBRANCE therapy, at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated [see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION]. Immune Infections IBRANCE may predispose patients to infections. Infections have been more frequently reported in patients treated with IBRANCE plus letrozole (55%) and in patients treated with IBRANCE plus fulvestrant (47%) than those treated in the respective comparator arms (34% and 31%, respectively). Grade 3 infections occurred in 5% of patients treated with IBRANCE plus letrozole and in no patients treated with letrozole alone. Grade 3 infections occurred in 3% of patients treated with either IBRANCE plus fulvestrant or placebo plus fulvestrant. Monitor patients for signs and symptoms of infection and treat as medically appropriate (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests). Physicians should be aware of the increased risk of infection with IBRANCE and should inform patients to promptly report any episodes of fever. Respiratory Pulmonary Embolism Pulmonary embolism has been reported in 5% of patients treated with IBRANCE plus letrozole and in 1% of patients treated with IBRANCE plus fulvestrant. There were no cases of pulmonary embolism in patients treated either with letrozole alone or placebo plus fulvestrant. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate. Drug-Drug Interactions CYP3A inhibitors: Concomitant use of IBRANCE and CYP3A inhibitors (e.g. clarithromycin, itraconazole, ritonavir, ketoconazole, grapefruit or grapefruit juice) may increase exposure to palbociclib. In patients receiving IBRANCE, coadministration of a strong CYP3A inhibitor should be avoided (see DRUG INTERACTIONS). CYP3A substrates: Concomitant use of IBRANCE and a CYP3A substrate may increase exposure to the CYP3A substrate. Caution is warranted when IBRANCE is co-administered with CYP3A substrates of narrow therapeutic index, such as alfentanil, cyclosporine, dihydroergotamine, or ergotamine (see DRUG INTERACTIONS). CYP3A inducers: Concomitant use of IBRANCE and CYP3A inducers (e.g. strong inducers such as rifampin, carbamazepine, phenytoin, St John s Wort, and moderate inducers such as nafcillin, bosentan, modafinil) may decrease palbociclib plasma concentration. In patients receiving IBRANCE, coadministration of strong CYP3A inducers should be avoided (see DRUG INTERACTIONS). IBRANCE Product Monograph Page 7 of 45

8 Sexual Function/Reproduction No clinical data have been obtained on fertility in humans. There were no effects on estrous cycle or mating and fertility in female rats in nonclinical studies [see Special Populations]. Based on nonclinical safety findings, male fertility may be impaired by treatment with IBRANCE [see PART II TOXICOLOGY, Reproductive and Developmental Toxicity]. Men should consider sperm preservation prior to beginning therapy with IBRANCE [see Special Populations]. Special Populations: Pregnant Women: There are no adequate and well-controlled studies using IBRANCE in pregnant women. IBRANCE may cause fetal harm when administered to a pregnant woman. In animal studies, palbociclib was shown to be fetotoxic in pregnant rats and rabbits [see PART II TOXICOLOGY]. IBRANCE should not be used during pregnancy and is indicated for use in postmenopausal women. If IBRANCE is used in women of childbearing potential, advise the patient to avoid becoming pregnant. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. If females of childbearing potential are receiving this drug they should use adequate contraceptive methods during therapy and for at least 21 days after completing therapy. Nursing Women: It is not known whether palbociclib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the patient. Pediatrics (< 18 years of age): The safety and efficacy of IBRANCE in children and adolescents <18 years have not been studied. Geriatrics ( 65 years of age): Population pharmacokinetic analysis was performed on data from 183 patients with cancer in an age range from 22 to 89 years. There was no clinically important difference in palbociclib exposure in patients 65 years of age compared with patients <65 years of age. In IBRANCE plus letrozole-treated patients, all grade neutropenia and leukopenia were reported more frequently in patients 65 years of age than in those <65 years of age (neutropenia: 81% vs. 70%, respectively; Grade 3/4: 57% vs. 52%; leukopenia: 54% vs. 35%, respectively), whereas similar incidences were reported for these parameters in both age groups in patients treated with IBRANCE plus fulvestrant. Hepatic Impairment: Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment, mild hepatic impairment had no IBRANCE Product Monograph Page 8 of 45

9 effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment. Renal Impairment: Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment and 29 patients had moderate renal impairment, mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment or requiring hemodialysis. Monitoring and Laboratory Tests Patients treated with IBRANCE should be monitored for signs and symptoms of myelosuppression, infection, and pulmonary embolism. Dose modification may be required [see Dosage and Administration]. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating complete blood count monitoring one week later. For patients who develop Grade 3 or 4 neutropenia, refer to the dose modification tables [see Dosage and Administration]. NOC/c ADVERSE REACTIONS Adverse Drug Reaction Overview The safety of IBRANCE has been assessed in 2 randomized studies of patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer. The most common adverse drug reactions of any grade reported in 10% of patients receiving palbociclib in combination with endocrine treatment were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, thrombocytopenia, diarrhea, alopecia, vomiting, decreased appetite, and rash. Most patients treated with IBRANCE (palbociclib) experienced myelosuppressive effects with over half experiencing Grade 3 neutropenia at some point during treatment. Thrombocytopenia and anemia were less commonly observed. Myelosuppressive effects can be expected to occur from Cycle 1 forward. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. IBRANCE Product Monograph Page 9 of 45

10 The adverse reactions are listed by system organ class, frequency category and grade of severity. Frequency categories are defined as: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Randomized Phase 2 Study (PALOMA-1) The safety of IBRANCE (125 mg/day for 21 consecutive days followed by 7 days off treatment) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated primarily in a randomized, controlled, Phase 2 trial (PALOMA-1). The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of IBRANCE in the Phase 2 portion of PALOMA-1. Patients were randomized 1:1 to receive the combination IBRANCE plus letrozole versus letrozole alone. The most common (>10%) adverse drug reactions of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (5%) and diarrhea (2%). Discontinuation and dose reduction due to AEs Dose reductions due to an adverse event of any grade occurred in 39% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole. Permanent discontinuation due to an adverse event occurred in 12 of 83 (15%) patients receiving IBRANCE plus letrozole, and in 2 of 77 (3%) patients receiving letrozole alone. Treatment-emergent adverse events presented in Table 1 below are based on a median duration of treatment of 13.8 months for patients on the IBRANCE plus letrozole arm, and 7.6 months for patients on the letrozole alone arm. IBRANCE Product Monograph Page 10 of 45

11 Table 1. Adverse Reactions Reported for Patients Who Received IBRANCE plus Letrozole or Letrozole Alone in PALOMA-1 IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) System Organ Class All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Any Adverse Drug Reaction % % % % % % Infections and infestations URI a Blood and lymphatic system disorders Neutropenia Leukopenia Anemia Thrombocytopenia Metabolism and nutrition disorders Decreased appetite Nervous system disorders Peripheral neuropathy b Dysgeusia Respiratory, thoracic and mediastinal disorders Epistaxis Gastrointestinal disorders Stomatitis c Nausea Diarrhea Vomiting Skin and subcutaneous tissue disorders Alopecia 22 N/A N/A 3 N/A N/A General disorders and administration site conditions Fatigue Asthenia Pyrexia Median duration of treatment (months) 14 8 Grading according to CTCAE 3.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; PT=preferred term; URI=Upper respiratory infection. a URI includes the following PTs: Influenza, Influenza like illness, Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Upper respiratory tract infection. b Peripheral neuropathy includes the following PTs: Neuropathy peripheral, Peripheral sensory neuropathy. c Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. IBRANCE Product Monograph Page 11 of 45

12 Abnormal Hematologic and Clinical Chemistry Findings Table 2. Incidence of Hematology Laboratory Abnormality for Patients Who Received IBRANCE Plus Letrozole or Letrozole Alone in PALOMA-1 Laboratory Abnormality IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) All All Grade 3 Grade 4 Grade 3 Grade 4 Grades Grades % % % % % % White blood cells decreased Neutrophils decreased Lymphocytes decreased Hemoglobin decreased Platelets decreased N=number of subjects. Randomized Phase 3 Study (PALOMA-3) The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in a randomized, controlled, Phase 3 trial (PALOMA-3). The data described below reflect exposure to IBRANCE in 345 out of 517 patients with HR-positive, HER2- negative metastatic breast cancer who received at least 1 dose of IBRANCE in PALOMA-3. Patients were randomized 2:1 to receive the combination IBRANCE plus fulvestrant versus placebo plus fulvestrant. The most common adverse reactions ( 10%) of any grade reported in patients in the IBRANCE plus fulvestrant arm were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia. The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%). Adverse reactions reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in PALOMA-3 are listed in Table 3. Discontinuation and dose reduction due to AEs Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus fulvestrant. No dose reduction was allowed for fulvestrant in PALOMA-3. Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%). IBRANCE Product Monograph Page 12 of 45

13 Treatment-emergent adverse events presented in Table 3 below are based on a median duration of treatment of approximately 5 months for patients on the IBRANCE plus fulvestrant arm, and approximately 4 months for patients on the placebo plus fulvestrant arm. IBRANCE Product Monograph Page 13 of 45

14 Table 3. Adverse Events* Reported (With a Frequency of 5% on the IBRANCE Arm) for Patients Who Received IBRANCE Plus Fulvestrant or Placebo Plus Fulvestrant in PALOMA-3 Adverse Reaction IBRANCE plus Fulvestrant (N=345) Placebo plus Fulvestrant (N=172) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Infections and infestations Infections a 34 1 < Blood and lymphatic system disorders Neutropenia b <1 Leukopenia c < Anemia d Thrombocytopenia e 19 2 < Metabolism and nutrition disorders Decreased appetite 13 < Psychiatric disorders Insomnia 11 < Nervous system disorders Headache 21 < Dysgeusia Dizziness 11 < Respiratory, thoracic and mediastinal disorders Epistaxis Cough Dyspnoea Gastrointestinal disorders Nausea <1 0 Stomatitis f 25 < Diarrhea <1 0 Constipation Vomiting 15 < <1 0 Abdominal Pain 6 < Skin and subcutaneous tissue disorders Alopecia 15 N/A N/A 6 N/A N/A Rash g 14 < General disorders and administration site conditions Fatigue Asthenia Pyrexia 9 < Oedema peripheral SOC Investigations Aspartate aminotransferase increased IBRANCE Product Monograph Page 14 of 45

15 * Adverse events reported with a frequency of 5% on the IBRANCE arm and a higher frequency on the IBRANCE arm compared to the placebo arm Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable. a Infections includes any reported PTs that are part of the System Organ Class Infections and infestations. b Neutropenia includes: neutropenia and neutrophil count decreased c Leukopenia includes: leukopenia and white blood cell count decreased d Anemia includes: anaemia, haemoglobin decreased, and hematocrit decreased e Thrombocytopenia includes: thrombocytopenia and platelet count decreased f Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. g Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption. Additional adverse reactions occurring at an overall incidence of <5% of patients receiving IBRANCE plus fulvestrant in Study PALOMA-3 included dry skin (4.9%), Vision blurred (4.9%), alanine aminotransferase increased (4.6%), lacrimation increased (4.3%), dry eye (2.9%), and febrile neutropenia (0.6%). Abnormal Hematologic and Clinical Chemistry Findings Table 4. Incidence of Hematology Laboratory Abnormality for Patients Who Received IBRANCE Plus Fulvestrant or Placebo Plus Fulvestrant in PALOMA-3 Laboratory Abnormality IBRANCE + Fulvestrant (N=345) Placebo Plus Fulvestrant (N=172) All All Grade 3 Grade 4 Grades Grades Grade 3 Grade 4 % % % % % % White blood cells decreased <1 Neutrophils decreased Anemia Platelets decreased N=number of subjects. Updated safety data for patients on the IBRANCE plus fulvestrant arm, based on an approximate 6-month increase in the median duration of treatment, were generally consistent with the safety table provided in Tables 3 and 4. No new safety concerns have been identified. IBRANCE Product Monograph Page 15 of 45

16 DRUG INTERACTIONS Overview Palbociclib is a substrate and weak inhibitor of CYP3A. It is also a moderate substrate of P- glycoprotein (P-gp) in vitro. Drug interactions were observed when IBRANCE (palbociclib) was coadministered with a strong CYP3A inhibitor and a strong CYP3A inducer. The aqueous solubility of palbociclib is ph-dependent. Drug interaction was observed when IBRANCE was coadministered with proton pump inhibitors (PPIs) under fasted conditions but was limited when IBRANCE was coadministered with PPIs under fed conditions. Food intake reduced the variability of palbociclib exposure. In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations. Drug-Drug Interactions Agents that may increase palbociclib plasma concentrations CYP3A Inhibitors: Data from a study in 12 healthy subjects indicate that coadministration of multiple 200 mg daily doses of itraconazole with a single 125 mg IBRANCE dose increased palbociclib total exposure (area under the curve, AUC inf ) and the peak exposure (C max ) by approximately 87% and 34%, respectively, relative to a single 125-mg IBRANCE dose given alone. The concomitant use of strong CYP3A inhibitors including, but are not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided. Agents that may decrease palbociclib plasma concentrations CYP3A Inducers: Data from a study in 14 healthy subjects indicated that coadministration of multiple 600 mg doses of rifampin, a strong CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUC inf and C max by 85% and 70%, respectively, relative to a single 125 mg IBRANCE dose given alone. The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John s wort, should be avoided. Data from a drug interaction study in healthy subjects (N=14) indicated that coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUC inf and C max by 32% and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone. If concomitant use of IBRANCE with moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) cannot be avoided, no dosing adjustments are required for IBRANCE. Antacids: Data from a study in healthy subjects indicated that coadministration of a single 125 mg dose of IBRANCE with multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed conditions decreased palbociclib C max by 41%, but had limited impact on AUC inf (13% decrease) compared with a single dose of IBRANCE administered alone. Given the reduced IBRANCE Product Monograph Page 16 of 45

17 effect on gastric ph of H2 receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid reducing agents on palbociclib exposure under fed conditions is expected to be minimal. Data from another study in healthy subjects indicated that coadministration of a single 125 mg dose of IBRANCE with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUC inf and C max by 62% and 80%, respectively, when compared with a single dose of IBRANCE administered alone. IBRANCE should be taken with food. Drugs That May Have Their Plasma Concentrations Altered by Palbociclib CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state in humans. In a study in 26 healthy subjects, coadministration of midazolam with multiple doses of IBRANCE increased the midazolam AUC inf and the C max values by 61% and 37%, respectively, as compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure. Luteinizing Hormone Releasing Hormone (LHRH) Agonists Data from a clinical study in patients with breast cancer showed that there was no clinically relevant drug interaction between palbociclib and goserelin when the 2 drugs were coadministered. Drug-drug interaction studies between palbociclib and other LHRH agonists have not been performed. In vitro studies with transporters In vitro evaluations indicated that palbociclib has a low potential to inhibit the activities of drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 at clinically relevant concentrations. In vitro studies demonstrate that palbociclib is not a substrate of OATP1B1 or OATP1B3. Drug-Food Interactions Grapefruit, grapefruit juice, and products containing grapefruit extract may increase palbociclib plasma concentrations and should be avoided. The effect of food on palbociclib exposure was evaluated in healthy subjects. Compared to IBRANCE given under overnight fasted conditions, the AUC inf and C max of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when moderate-fat food was given 1 hour before and 2 hours after IBRANCE dosing. In addition, food intake significantly reduced the inter-subject and intrasubject variability of palbociclib exposure. Based on these results, IBRANCE should be taken with food. IBRANCE Product Monograph Page 17 of 45

18 Drug-Herb Interactions Interactions with herbal products have not been established. St. John s wort (Hypericum perforatum) is an inducer of CYP3A4/5 that may decrease palbociclib plasma concentrations and should be avoided. Drug-Laboratory Interactions Interactions between IBRANCE and laboratory tests have not been studied. Drug-Lifestyle Interactions Interactions between IBRANCE and lifestyle have not been studied. NOC/c DOSAGE AND ADMINISTRATION Dosing Considerations Pre/perimenopausal women treated with the combination IBRANCE plus fulvestrant therapy should be treated with luteinizing hormone releasing hormone (LHRH) agonists according to local clinical practice. Recommended Dose and Dosage Adjustment The recommended dose of IBRANCE (palbociclib) is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food. Patients should be advised to take their dose at approximately the same time each day. Continue the treatment as long as the patient is deriving clinical benefit from therapy. IBRANCE is used in combination with letrozole or fulvestrant. For full dosing instructions of letrozole or fulvestrant, please consult the corresponding Product Monographs. Management of some adverse reactions may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation of IBRANCE as per dose reduction schedules provided in Table 5, 6 and 7. Table 5. IBRANCE Recommended Dose Modification for Adverse Events Dose Level Recommended starting dose First dose reduction Second dose reduction Dose 125 mg/day 100 mg/day 75 mg/day* *If further dose reduction below 75 mg/day is required, discontinue palbociclib treatment. IBRANCE Product Monograph Page 18 of 45

19 Table 6. Dose Modification and Management Hematologic Toxicities a Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first 2 cycles, and as clinically indicated. CTCAE Grade Grade 1 or 2 Grade 3 Grade 3 neutropenia b with fever 38.5 ºC and/or infection Dose Modifications No dose adjustment is required. Day 1 of cycle: Withhold IBRANCE, repeat complete blood count monitoring within 1 week. When recovered to Grade 2, start the next cycle at the same dose. Day 14 of first 2 cycles: Continue IBRANCE at current dose to complete cycle. Repeat complete blood count on Day 21. Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia in subsequent cycles. Withhold IBRANCE until recovery to Grade 2. Resume at the next lower dose. Grade 4 Withhold IBRANCE until recovery to Grade 2. Resume at the next lower dose. Grading according to CTCAE 4.0 CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal. a Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). b Absolute neutrophil count (ANC): Grade 1: ANC < LLN /mm 3 ; Grade 2: ANC <1500/mm 3 ; Grade 3: ANC <1000/mm 3 ; Grade 4: ANC <500/mm 3. Table 7. IBRANCE Dose Modification and Management Non-Hematologic Toxicities CTCAE Grade Grade 1 or 2 Grade 3 non-hematologic toxicity (if persisting despite medical treatment) Grading according to CTCAE 4.0 CTCAE=Common Terminology Criteria for Adverse Events. b. Dose Modifications No dose adjustment is required. Withhold until symptoms resolve to: Grade 1; Grade 2 (if not considered a safety risk for the patient) Resume at the next reduced dose level. IBRANCE Product Monograph Page 19 of 45

20 No dose adjustments are required on the basis of age, gender, or body weight [see Special Populations]. Missed Dose If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. Special populations Hepatic impairment: No dose adjustments are required for patients with mild hepatic impairment (total bilirubin upper limit of normal (ULN) and aspartate transaminase (AST) >ULN, or total bilirubin >1.0 to 1.5 ULN and any AST). IBRANCE has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN and any AST) [see Pharmacokinetics, Special Populations and Conditions]. Renal impairment: No dose adjustments are required for patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30 ml/min). IBRANCE has not been studied in patients with severe renal impairment (CrCl <30 ml/min) or requiring hemodialysis [see Pharmacokinetics, Special Populations and Conditions]. OVERDOSAGE There is no known antidote for IBRANCE (palbociclib). The treatment of overdose of IBRANCE should consist of general supportive measures. For management of a suspected drug overdose, contact your regional Poison Control Centre. NOC/c ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action Palbociclib is a selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation. Through inhibition of cyclin D-CDK4/6 complex activity, palbociclib inhibits the phosphorylation of retinoblastoma (Rb) protein, blocking cell cycle progression from G1 into S phase. In a panel of molecularly profiled breast cancer cell lines, palbociclib exhibited the greatest efficacy towards the luminal ER-positive subtype; particularly, in cell lines with increased Rb and cyclin D1 and decreased p16 gene expression. In combination with anti-estrogen agents, palbociclib demonstrated enhanced inhibition of cell proliferation and induction of cell senescence in ER-positive breast cancer models. IBRANCE Product Monograph Page 20 of 45

21 Pharmacodynamics A pharmacokinetic/pharmacodynamic analysis was conducted using data from 184 patients with advanced cancer to evaluate the relationship between heart rate corrected QT interval according to study-specific criteria (QTcS) and palbociclib concentration. A positive correlation was observed between QTcS and palbociclib concentration, with a mean QTcS increase of 5.60 msec, and upper bound 1-sided 95% confidence interval of 8.72 msec at the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (i.e., 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days). Pharmacokinetics The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects. Pharmacokinetic parameters of palbociclib and letrozole obtained from study A are shown in Table 8. Table 8 Summary of Plasma Pharmacokinetic Parameters of Palbociclib (125 mg QD) and Letrozole (2.5 mg QD) at Steady State When Administered Alone or in Combination to Patients with Advanced Breast Cancer in the Phase 1 Portion of A Palbociclib PK Parameter Summary Statistics a Treatment C max (ng/ml) AUC (0-24) (ng.hr/ml) Tmax (hr) t ½ (hr) CL/F (L/hr) V z F (L) PLB alone (N=12) 116 (28) 1982 (29) 7.9 ( ) 28.8 (±5.0) 63.1 (29) 2583 (26) PLB + LTZ (N=12) 108 (29) 1933 (31) 7.9 ( ) Letrozole PK Parameter Summary Statistics a LTZ alone (N=12) 104 (31) 1936 (35) 1.0 (0-4.4) LTZ + PLB (N=12) 95.0 (27) 1739 (30) 2.0 ( ) AUC (0-24) =area under the plasma concentration-time curve from time 0 to 24 hours after dosing; CL/F=apparent oral clearance; C max =maximum observed plasma concentration; CSR=Clinical Study Report; %CV=percent coefficient of variation; LTZ=letrozole; N=total number of patients in the treatment arm; PK=pharmacokinetic; PLB=Palbociclib; QD=once daily; Std Dev=standard deviation; T max =time to first occurrence of C max ; t 1/2 =terminal plasma half-life; V z /F=apparent volume of distribution. a. Geometric mean (geometric %CV) is shown for all PK parameters except median (range) for T max and arithmetic mean (±Std Dev) for t 1/2. Absorption: Following oral single-dose administration, palbociclib was absorbed with median time to achieve C max of 4 to 8 hours. The mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and C max increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range ). Food effect: The effect of food on palbociclib exposure was evaluated in healthy subjects. Compared to IBRANCE given under overnight fasted conditions, the AUC inf and C max of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when moderate-fat food was given 1 hour before IBRANCE Product Monograph Page 21 of 45

22 and 2 hours after IBRANCE dosing. In addition, food intake significantly reduced the intersubject and intra-subject variability of palbociclib exposure. Based on these results, IBRANCE should be taken with food. Proton pump inhibitors effect: In a healthy subject study, coadministration of a single dose of IBRANCE with the PPI rabeprazole under fed conditions decreased palbociclib C max by 41%, but had limited impact on AUC inf (13% decrease), when compared to a single dose of IBRANCE administered alone. In another healthy subject study, coadministration of a single dose of IBRANCE with the PPI rabeprazole under fasted conditions decreased palbociclib AUC inf and C max by 62% and 80%, respectively, when compared to a single dose of IBRANCE administered alone. Distribution: Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence over the concentration range of 500 ng/ml to 5000 ng/ml. The geometric mean apparent volume of distribution (V z /F) was 2583 L. Metabolism: In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [ 14 C]palbociclib to humans, the major primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23% of total radioactivity in plasma). The major circulating metabolite was a glucuronide conjugate of palbociclib (14.8% of total radioactivity in plasma), although it only represented 1.5% of the administered dose in the excreta. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 25.8% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulfotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib. Excretion: The geometric mean apparent oral clearance (CL/F) of palbociclib was L/hr, and the mean plasma elimination half-life was 28.8 hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [ 14 C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites. Excretion of unchanged palbociclib in feces and urine was 2.3% and 6.9% of the administered dose, respectively. Special Populations and Conditions: Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), sex had no effect on the exposure of palbociclib, and neither age nor body weight had a clinically important effect on the exposure of palbociclib. IBRANCE Product Monograph Page 22 of 45

23 Pediatric Use Pharmacokinetics of palbociclib have not been evaluated in children and adolescents <18 years of age. Hepatic Impairment Based on a population pharmacokinetic analysis that included 183 patients with cancer, where 40 patients had mild hepatic impairment (total bilirubin ULN and AST > ULN or total bilirubin >1.0 to 1.5 ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN and any AST). Renal Impairment Based on a population pharmacokinetic analysis that included 183 patients with cancer, where 73 patients had mild renal impairment (60 ml/min CrCl <90 ml/min) and 29 patients had moderate renal impairment (30 ml/min CrCl <60 ml/min), neither mild nor moderate renal impairment had an effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment or requiring hemodialysis. About 17.5% of IBRANCE and its metabolites are excreted via the kidney. Japanese population Data from a pharmacology study evaluating the effect of Japanese ethnicity on the PK of a single 125-mg oral palbociclib dose given to Japanese and non-asian healthy volunteers indicate that palbociclib AUC inf and C max values were 30% and 35% higher, respectively, in Japanese subjects when compared with non-asian subjects. STORAGE AND STABILITY Store at 20 o C to 25 o C; excursions permitted between 15 o C to 30 o C. SPECIAL HANDLING INSTRUCTIONS Any unused product or waste material should be disposed in accordance with local requirements. DOSAGE FORMS, COMPOSITION AND PACKAGING IBRANCE (palbociclib) is supplied in the following strengths and package configurations: IBRANCE Product Monograph Page 23 of 45

24 IBRANCE Capsules Package Configuration Capsule Strength (mg) Capsule Description Bottles of 21 capsules 125 opaque, hard gelatin capsules, size 0, with caramel cap and body, printed with white ink Pfizer on the cap, PBC 125 on the body Bottles of 21 capsules 100 opaque, hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink Pfizer on the cap, PBC 100 on the body Bottles of 21 capsules 75 opaque, hard gelatin capsules, size 2, with light orange cap and body, printed with white ink Pfizer on the cap, PBC 75 on the body List of excipients Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. The light orange, light orange/caramel and caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron oxide, and titanium dioxide; and the printing ink contains shellac, titanium dioxide, ammonium hydroxide, propylene glycol and simethicone. IBRANCE Product Monograph Page 24 of 45

25 PART II: SCIENTIFIC INFORMATION IBRANCE, indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization. For further information for IBRANCE please refer to Health Canada s Notice of Compliance with conditions - drug products web site: IBRANCE, indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed after prior endocrine therapy, has been issued marketing authorization without conditions. PHARMACEUTICAL INFORMATION Drug Substance Common name: Palbociclib Chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2- yl]amino}pyrido[2,3-d]pyrimidin-7(8h)-one Molecular formula and molecular mass: C 24 H 29 N 7 O 2, Daltons Structural formula: Me Me N O HN N N O N N N H IBRANCE Product Monograph Page 25 of 45